Objective To investigate the efficacy of Shengmai Powder and Liuwei Dihuang Pill modified formula combined with glimepiride in the treatment of type 2 diabetes mellitus (T2DM) with Qi-Yin deficiency pattern. Methods A total of 95 T2DM patients with Qi-Yin deficiency pattern admitted to Ruichang Hospital of Traditional Chinese Medicine in Jiangxi Province from February 2022 to February 2024 were selected and randomly divided into a control group (47 cases) or an observation group (48 cases) by a random number table method. The control group was treated with glimepiride, based on which the observation group was additionally given Shengmai Powder and Liuwei Dihuang Pill modified formula. The therapeutic effects, blood glucose, blood lipid, and inflammatory index levels after 12 weeks of treatment, as well as the occurrence of adverse reactions, were compared between the two groups. Results After 12 weeks of treatment, the total effective rate of the observation group was higher than that of the control group; the levels of fasting blood glucose, 2-hour postprandial blood glucose, glycosylated hemoglobin, total cholesterol, triglyceride, interleukin-6, tumor necrosis factor-α, and C-reactive protein in the observation group were lower than those in the control group, while the level of apolipoprotein A1 was higher than that in the control group (all P<0.05). There was no statictically significant difference in the adverse reaction rate between the two groups (P>0.05). Conclusion Shengmai Powder and Liuwei Dihuang Pill modified formula combined with glimepiride has a definite efficacy in the treatment of T2DM with Qi-Yin deficiency pattern. It can better reduce blood glucose levels, regulate blood lipid levels, alleviate inflammatory reactions, and has high safety.